Topical α-1-antitrypsin, non-aqueous lipid miscible, benzalkonium chloride compositions for treating skin

ABSTRACT

The invention provides a pharmaceutical composition for the treatment of a mammal having a skin disease. The composition contains a serine protease inhibitor and an effective amount of a cationic quaternary ammonium salt at a concentration below the critical micelle concentration for increasing the penetration of the inhibitor in the skin. Additionally, these may be included an ethoxylated nonylphenol.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical preparations containingserine protease inhibitors for use in topical applications. Moreparticularly, the invention provides preparations for increasing thepenetration of serine protease inhibitors when applied to the skin.

BACKGROUND OF THE INVENTION

Topical therapy permits drug application to a specific disease site inhigh concentrations with little systemic influence. This can yield moreefficient dosages which minimizes the potential of side effects.

The percutaneous absorption of a drug varies greatly dependant onnumerous factors. Little quantitative data is available on permeation ofspecific drugs, but there is a general knowledge of the issues whicheffect permeation of the skin. The principal barrier to permeation isthe stratum corneum. It is desirable to provide a topical dosage formwhich will be physically and chemically stable, cosmetically acceptableto the patient, and adequately/efficiently transport the active drug tothe site of action. This is difficult when the drug is a natural proteinwhich degrades when standing over a period of time in warm weather andeven at room temperature.

The search for a suitable vehicle for serine protease inhibitors musttake into account the following parameters:

1. Compatibility

2. Stability

3. Physiological Inertness

4. Promotion of Bioavailabiity

5. Easy Spreadability

6. Resistance to Microbial Growth

7. Sufficient Capacity

8. Cosmetic Acceptability

The ideal vehicle would be one that is very stable and would withstandstorage over a considerable period of time and temperature range withoutdeterioration.

The ideal vehicle should be relatively inert pharmacologically andphysiologically. An exception is a base that moisturizes or hydrates thedermis and thereby increases penetration. If the vehicle eithermoisturizes the skin directly or prevents the loss of moisture from theskin, it may enhance permeation of the drug. In this scenario, thephysiological action of the vehicle would be desirable and beneficial.

Otherwise, it is important that the vehicle have little or no effect onthe skin. It should be free of irritating or sensitizing properties. Theideal vehicle should be non-reactive with the drug itself. In otherwords the vehicle should not interfere with the bioavailability of thedrug and if possible it should promote the absorption of the drug by thebase.

The components of the base must be compatible with each other.Surfactants, emulsifying agents, and preservatives must all becompatible with each other as well as with the drug if they are to beused successfully.

For clinical purposes it is advisable to have a vehicle that will remainstable for at least six months, that requires no major compounding atthe time of dispensing and will remain stable at a temperature rangeroughly between 5 and 50 degrees Centigrade.

The vehicle itself should have no physiological action apart from itsrole of carrying the active ingredient. Ideally, we are seeking an agentthat is neither irritating or sensitizing.

If the drug, namely the serine protease inhibitor, is to be effectivetopically it must be available to penetrate the dermis. This means itmust be released by the base or carried with the base across the skinbarrier. If the skin is intact, the base may facilitate this action bysoftening or hydrating the superficial epidermal tissue if that tissuehas become dry, cracked or impervious to penetration. Theoretical anideal base could alter the membrane permeability of the skin. The actualpermeability of skin to a number of drugs is accurately correlated withthe water solubility and mineral oil/water partition coefficient of thedrug. Ionization of the drug is also a very important factor so the pHof both the drug and the vehicle must be taken into consideration.

The efficacy of any topical medication is dependant on the intimatecontact of the vehicle and drug with the skin. A vehicle which will notcoat or spread evenly is not capable of providing the free and closecontact we desire.

Frequently, ointment and cream bases have turned out to be excellentgrowth mediums for bacteria. This is definitely undesirable and possiblecontamination of the skin cannot be risked. We need to consider thevarious antibacterials and preservatives available in light of thecharacteristics of the drug itself.

It is not only essential that the vehicle meet all of the abovequalification, it must be capable of holding a sufficient concentrationof the drug in a homogenous state and reasonable volume.

Cosmetic acceptability involves several areas of concern. A topicalproduct should be easily applied to the skin. It is essential that thevehicle be readily spreadable to assure compliance and to avoidirregular concentrations of the drug on the skin because of unevenapplication of the preparation. The ease of application and removal ofthe vehicle can determine whether or not the treatment program isadhered to. The frequency of application if another property that mustbe considered. Properties of the vehicle can determine if the drug mustbe applied frequently, it may be easily removed by evaporation,friction, etc. A vehicle that requires prolonged soaks or wet dressingscan also negatively affect compliance. Vehicles that feel sticky, greasyor slimy, that stain clothes, skin and everything else that is touchedare also not acceptable. Additional problems with compliance can occurif the vehicle is not cosmetically pleasant or acceptable to thepatient. It is preferable to have a vehicle that not only feels pleasanton the skin, but one that does not bring attention to its use. In thisparticular context color and odor are very important characteristics.

SUMMARY OF THE INVENTION

According to the present invention there is provided a pharmaceuticalvehicle for the topical application of a serine protease inhibitor whichpermits prolonged activity of the inhibitor at the site of applicationand improved penetration. The improved penetration is provided with avehicle comprising a hydrophilic ointment base of petrolatum, mineraloil, mineral wax, wax wool alcohol, water and a cationic quaternaryammonium salt. More specifically the vehicle contains about 20 to 50% byweight of petrolatum, about 5 to 20% by weight of mineral oil, about 0to 20% by weight of mineral wax, about 0 to 10% by weight of wax woolalcohol, about 1 to 5% by weight of water and about 0,001 to 0.05% byweight of a cationic quaternary ammonium salt, especially, benzalkoniumchloride.

The preparation preferably is used to prepare a formulation containingabout 2 to 10% by weight of serine protease inhibitor and maintain thesurfactant below the critical micelle concentration. It has beensurprisingly found that there is a synergism when the cationicquaternary ammonium salt is used in combination with an ethoxylatednonylphenol.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides an improvement in topically appliedcompositions containing a serine protease inhibitor which is used totreat skin conditions in mammals, for example, atopic dermatitis,psoriasis, contact dermatitis, and the like. More particularly, acationic quaternary ammonium salt is used to break the surface tensionresulting from the carrier and to permit improved penetration of theserine protease inhibitor into the skin. A small amount of thequaternary ammonium salt, is required, preferably about 0.001 to 0.05%by weight of the composition. Surprisingly, the addition of anethoxylated nonylphenol provides a synergistic effect of greaterpenetration of the serine protease inhibitor. An amount of about 0.001to 0.05% by weight of ethoxylated nonylphenol is usually sufficient.However, the combination of quaternary ammonium salt and ethoxylatednonylphenol must be below the critical micelle concentration.

The quaternary ammonium salt has been found to be particularly usefulwith a vehicle comprising a hydrophilic ointment base of petrolatum,mineral oil, mineral wax, wax wool alcohol and water. A preferredvehicle comprises about 20 to 50% by weight of petrolatum, about 5 to20% by weight of mineral oil, about 0 to 20% by weight of mineral wax,about 0 to 10% by weight of wool wax alcohol, about 1 to 5% by weight ofwater, about 0.001 to 0.05% by weight of a cationic quaternary ammoniumsalt, and optionally, about 0,001 to 0.05% by weight of an ethoxylatednonylphenol.

Illustrative nonoinic surfactants having the desired characteristics forformulation are available on the market under the tradename of "NEODOL"products by Shell Oil Company; "TERGITOL" products by Union CarbideCompany; and "ALFOL" products by Continental Oil Company. Specificexamples include "NEODOL 25-7" (linear C₁₂ -C₁₅ primary alcoholcondensed with 7 moles of ethylene oxide per mole of alcohol); "NEODOL45-7" (linear C₁₄ -C₁₅ primary alcohol mixture condensed with 7 moles ofethylene oxide per mole of alcohol); "TERGITOL" having the formula C₉H₁₉ C₆ H₄ (OCH₂ CH₂)_(n) OH wherein n is 8 to 10, preferably an averagevalue of 9, and is condensed with 5 to 8 moles of ethylene oxide.

The cationic quaternary ammonium salts which include a greater number ofshort-chain alkyl groups in the structure, incline toward betterproperties. Specific examples of such compounds that may be used in thecompositions of this invention include di-isobutyl cresoxy ethoxy ethyldimethyl benzyl ammonium chloride, di-isobutyl phenoxy ethoxy ethyldimethyl benzyl ammonium chloride, myristyl dimethylbenzene ammoniumchloride, benzalkonium chloride, cetyl pyridinium chloride, coconutdimethyl benzyl ammonium chloride, stearyl dimethyl benzyl ammoniumchloride, alkyl dimethyl benzyl ammonium chloride, alkyl diethyl benzylammonium chloride, alkyl dimethyl benzyl ammonium bromide, di-isobutylphenoxy ethoxy ethyl trimethyl ammonium chloride, di-isobutyl phenoxyethoxy ethyl dimethyl alkyl ammonium chloride, methyl-dodecylbenzyltrimethyl ammonium chloride, cetyl trimethyl ammonium bromide, octadecyldimethyl ethyl ammonium bromide, cetyl dimethyl ethyl ammonium bromide,octadecenyl-9-dimethyl ethyl ammonium bromide, dioctyl dimethyl ammoniumchloride, dodecyl trimethyl ammonium chloride, octadecyl trimethylammonium chloride, octadecyl trimethyl ammonium bromide, hexadecynyltrimethyl ammonium iodine, octyltrimethyl ammonium fluoride, andmixtures thereof. Other water dispersible salts, such as the acetates,sulfates, nitrates, and phosphates, are effective in place of thehalides, but the chlorides and bromides are preferred.

The preferred quaternary ammonium salt for use in the invention isbenzalkonium chloride. The amount used is generally about 0,001 to 0.05%by weight of composition. The benzalkonium chloride is commerciallyavailable and is sold under the name "BARQUAT or quaternium-15."

The serine protease inhibitors which are contemplated in the presentinvention are any of the inhibitors, their analogs, derivates or saltsof the human type which can inhibit mast cells or bind with any one ormore of the protease derived from eosinophils, basophils and/orneutrophils such as elastase, cathepsin-G, tryptase, chymase, kinins,kallikrein, tumor necrosis factor, chymotrypsin, GEF, collagenase,inhibit IgE production and the like.

The serine protease inhibitors included in the present invention arehuman alpha 1-antichymotrypsin, alpha 1-antitrypsin, alpha2-macroglobulin, eglin, elastinal 1, elastin 3, eglin 2, C-reactiveprotein, beta 1-antigellagenase, serine amyloid A protein, alphacysteine protease inhibitors, inter-alpha-trypsin inhibitor, secretoryleucocyte protease inhibitor, bronchial mucous inhibitor, andC-1-inhibitor. The inhibitors of the invention may be natural orprepared by recombinant means. The recombinant may be glycosylated.

The use of alpha 1-antitrypsin and alpha 1-antichymotrypsin incombination with a corticosteroid has been especially useful in thetreatment of the various inflammatory skin conditions including thosewhich are induced by autoimmune disease, virus and bacterial infections.

The inhibitors of the invention may be derived from human blood orprepared by cloning, by conventional techniques utilizing anoligonucleotide probe or anti-body probe, and the like. The recombinantgene product of the invention is especially useful since it is free ofcontaminating viruses when produced.

The analogs, salts and derivatives may be formed utilizing conventionaltechniques associated with other proteins without effecting the utilityof the compound. There may be prepared the alkali metal salts,acid-addition salts, and esters similar to other proteins or peptides.

The following examples further illustrate the practice of thisinvention, but are not intended to be limiting thereof. It will beappreciated that the selection of actual amounts of specific serineprotease inhibitors and corticosteroids to be administered to anyindividual patient (human or animal) will fall within the discretion ofthe attending physician and will be prescribed in a manner commensuratewith the appropriate dosages will depend on the stage of the disease andlike factors uniquely within the purview of the attending physician.

The following formulations were prepared and assessed by the pharmacistand patient to determine a commerically acceptable vehicle having thebest penetration. Alpha 1-antitrypsin was used as representative serineprotease inhibitor because it had a common solubility and characteristicfor formulation.

    ______________________________________                                        Example                                                                       ______________________________________                                        FORMULA #1 Alpha 1-antitrypsin (α1-PI)                                             petrolatum                                                                    mineral oil                                                                   mineral wax                                                                   wool wax alcohol                                                              barquat                                                            Pharmacist assessment:                                                                     1.    One of the methods of formulation                                             was to incorporate the α-1-PI powder                                    into the ointment dry. This caused                                            the ointment to have a grainy                                                 texture, but the Alpha-1-PI was well                                          protected and preserved inside the                                            ointment. This preparation worked                                             well but the concentration needed to                                          be at least 5% in order to get a good                                         therapeutic response. This                                                    concentration caused the preparation                                          to cost about $130.00 per ounce.                                        2.    This time we hydrated the Alpha-1-PI                                          with 7 ml water per 1 gram vial and                                           incorporated this into the ointment                                           maintaining 5% concentration. This                                            preparation was smooth, looked more                                           pleasing and spread more evenly. The                                          therapeutic response was quicker                                              because the α-1-PI was pre-hydrated.                 Patient's assessment:                                                                     The patient's didn't like the graininess                                      of the ointment preparation from the dry                                      powder. They generally preferred the                                          ointment pre-hydrated but still objected                                      to the greasy feel.                                               ______________________________________                                        FORMULA #2 α1-PI                                                                   calamine precipitated                                                         diphenhydramine                                                               barquat                                                            Pharmacist assessment:                                                                     The dry pulverized Alpha-1-PI was                                             added to the solution in various                                              concentration. This preparation                                               was messy and would soil the                                                  patient's clothing. We rejected                                               it for this reason.                                              Patient's assessment:                                                                     The patient's felt the same way we did                                        about the messiness of this preparation.                          ______________________________________                                        FORMULA #3 α1-PI                                                                   8-Hydroxy-Quinolone sulfate 0.3%                                              petrolatum                                                                    lanolin                                                                       barquat                                                            Pharmacist assessment:                                                                     The α1-PI was incorporated into this                                    ointment both wet and dry. Either                                             preparation was pharmaceutically                                              acceptable, but was rejected because                                          the lanolin increased the potential                                           for and allergic reaction.                                       Patient's assessment:                                                                     The most common remarks were in                                               reference to the greasiness and strong odor                                   of this preparation.                                              ______________________________________                                        FORMULA #4 α1-PI                                                                   water        mineral oil                                                      propylene glycol                                                                           glyceryl stearate                                                PEG-100 stearate                                                                           PEG-40 stearate                                                  laureth-4    PEG-4-dilaurate                                                  lanolin oil  sodium acetate                                                   carbomer-934 trianolamine                                                     methylparaben                                                                              dioctyl Na sulfosuccinate                                        fragrance    acetic acid                                                                   barquat                                               Pharmacist assessment:                                                                     The powdered Alpha-1-PI was added to                                          this formula to form a smooth and                                             soothing lotion. This preparation                                             was a little to runny and had a very                                          strong odor that tended to linger.                                            This preparation was rejected for                                             these reasons.                                                   Patient's assessment:                                                                     The patient's comments were most often                                        centered of the objectional odor.                                 ______________________________________                                        FORMULA #5 α1-PI                                                                   coal tar 5%                                                                   hydro-alcoholic gel (13.8% alcohol)                                           barquat                                                            Pharmacist assessment:                                                                     The powdered α-1-PI was added to this                                   formula in various concentrations.                                            This preparation was smelly, messy                                            and would stain clothing. There is                                            a possibility that the alcohol in the                                         vehicle could be irritating and/or                                            drying to the patient's skin and                                              therefore undesirable. It was                                                 rejected for these reasons.                                      Patient's assessment:                                                                     This product was never assessed by a                                          patient.                                                          ______________________________________                                        FORMULA #6 α1-PI                                                                   water        propylene glycol                                                 mineral oil  isopropyl myristate                                              stearic acid glyceryl stearate                                                PEG-100 stearate                                                                           sunflower seed oil                                               tocopherol acetate                                                                         retinyl palmitate                                                ergocalciferol                                                                             lanolin alcohol                                                  triethanolamine                                                                            myristyl myristate                                               simethicone  carbomer-934                                                     cetyl alcohol                                                                              stearyl alcohol                                                  allantoin    methylparaben                                                    quaternium-15                                                                              propylparaben                                                    sorbic acid  fragrance                                                                     barquat                                               Pharmacist assessment:                                                                     The powered α-1-PI was added to this                                    formula in various concentrations.                                            This preparation was cosmetically                                             pleasing. It was smooth in texture                                            and would spread evenly. The                                                  fragrance and feel gave this                                                  preparation much appeal.                                         Patient's assessment:                                                                      The patients consider this preparation                                        quite good but the lotion was less                                            occlusive than was needed for some of                                         the patient's condition.                                         ______________________________________                                        FORMULA #7 α1-PI                                                                   urea 10%      water (scented)                                                 carbomer-940  cetyl alcohol                                                   isopropyl palmitate                                                                         PEG-8 dioleate                                                  PEG-8 distearate                                                                            propylene glycol                                                propy-gly diapelargonate                                                      stearic acid  trolamine                                                       xanthan gum   fragrance                                                       barquat                                                            Pharmacist assessment:                                                                     This formulation made a very good                                             preparation. It was smooth,                                                   pleasantly scented and occluded                                               the skin quite well.                                             Patient's assessment:                                                                     This formula was well accepted by                                             the patients. No negative comments                                            noted.                                                            ______________________________________                                        FORMULA #8 α1-PI                                                                               5%                                                                purified    5%     petrolatum                                                                             38.95%                                            water                                                                         mineral oil                                                                              20%     mineral wax                                                                              20%                                             wool wax   10%     barquat   0.05%                                            alcohol                                                                       metylchloroisothiazolinone-                                                   methylisothiazolinone 1%                                           Pharmacist assessment:                                                                     The dry powder was added to this                                              preparation. There was adequate                                               water to properly hydrate the                                                 α-1-PI. The preparation was very                                        smooth and spread very well. It was                                           a little more oily than some of the                                           other lotion.                                                    Patient's assessment:                                                                     This lotion was well accepted by the                                          patients. No negative comments were                                           recorded.                                                         ______________________________________                                        FORMULA #9 α1-PI                                                                   water          glycerin                                                       cetearyl alcohol                                                                             palm oil glyceride                                             ceteareth-20   mineral oil                                                    petrolatum     sorbitol                                                       avocado oil    glyceryl dilaurate                                             dimethicone    isopropyl palmitate                                            stearic acid   allantoin                                                                     nonoxynol-9                                                    squalene       methylparaben                                                  sodium carbomer-941                                                                          propylparaben                                                  quaternium-15  fragrance                                           Pharmacist assessment:                                                                     This lotion went on smooth and                                                vanished very quickly. No greasy                                              feeling remained. The color and                                               fragrance should be improved.                                    Patient's assessment:                                                                     Most patients liked the way this                                              preparation would vanish and not                                              leave a greasy residue.                                           ______________________________________                                        FORMULA #10                                                                              α1-PI                                                                   dimethicone 3% water                                                          petrolatum     glycerin                                                       steareth-2     cetyl alcohol                                                  benzyl alcohol laureth-23                                                     magnesium Al silicate                                                                        carbomer-934                                                   sodium hydroxide                                                                             quaternium-15                                       Pharmacist assessment:                                                                     This lotion was a little slower                                               vanishing than some. It tended                                                to stay wet longer than I like.                                               This preparation did not have very                                            much occlusion and seemed to be more                                          of a cleansing lotion. I did not                                              feel as if it would moisturize well                                           enough for most of our patients.                                 Patient's assessment:                                                                     The patient did not offer any complaints                                      on the feel of this lotion, but a few                                         objected to the fragrance.                                        Laureth-23 could be replaced by an ethoxylated nonylphenol.                   ______________________________________                                        FORMULA #11                                                                              α1-PI                                                                   menthol      camphor                                                          alum         salicylic acid                                                   phenol       fragrance                                                        petrolatum   lanolin                                                          cocoa butter wax base                                                         quaternium-15                                                      Pharmacist assessment:                                                                     This preparation would absorb very                                            little water, therefore the powder                                            needed to be blended dry. The                                                 fragrance was strong, the menthol was                                         cooling and it was very occlusive.                                            This preparation may be good for some                                         application, but it does not work                                             well for atopic dermatitis.                                      Patient's assessment:                                                                     Most of the patients thought the fragrance                                    was to strong and it was too greasy.                              ______________________________________                                        FORMULA #12                                                                              α1-PI                                                                   anhydrous lanolin plain                                                       barquat                                                            Pharmacist assessment:                                                                     This preparation had a strong odor                                            and was very greasy. I feel this                                              high concentration of lanolin may                                             cause some patients with wool                                                 allergies to react.                                              Patient's assessment:                                                                     The odor was too strong and it was too                                        greasy.                                                           ______________________________________                                        FORMULA #13                                                                              α1-PI                                                                   deodorized cocoa butter                                                       barquat                                                            Pharmacist assessment:                                                                     This preparation was firm and                                                 difficult to blend. We had to blend                                           the powder into it dry. This                                                  preparation occluded the skin very                                            well, but was difficult to work                                               with.                                                            Patient assessment:                                                                       This preparation was well accepted by the                                     patients.                                                         ______________________________________                                        FORMULA #14                                                                              α1-PI                                                                   water        mineral oil                                                      petrolatum   sorbitol                                                         lanolin      lanolin alcohol                                                  stearic acid triethanolamine                                                  butylparaben methylparaben                                                    propylparaben                                                                              sodium chloride                                                               quaterium-15                                          Pharmacist assessment:                                                                     This preparation was one of the                                               better occlusive lotions. It went on                                          smooth and made a very nice                                                   moisturizing agent.                                              Patient's assessment:                                                                     This preparation was generally well                                           accepted by the patients. No objections                                       were made to this lotion.                                         ______________________________________                                        FORMULA #15                                                                              α1-PI                                                                   mineral oil  water                                                            propylene glycol                                                                           glyceryl stearate                                                PEG-100 stearate                                                                           PEG-40 stearate                                                  PEG-4 dilaurate                                                                            laureth-4                                                        lanolin oil  methylparaben                                                    propylparaben                                                                              fragrance                                                        carbomer-934 triethanolamine                                                  dioctyl Na sulfosuccinate: quaternium-15                           Pharmacist assessment:                                                                     This preparation was a very good                                              lotion. It went on smooth but was                                             fluid enough to spread over large                                             areas. It was one of the more                                                 occlusive lotions. The fragrance and                                          texture was pleasant.                                            Patient's assessment:                                                                     This preparation was generally well                                           accepted by the patients. No negative                                         comments were noted.                                              ______________________________________                                        FORMULA #16                                                                              α1-PI                                                                   water        mineral oil                                                      lactic acid  sodium PCA                                                       isopropyl palmitate stearyl alcohol                                           ceteareth-20 sodium hydroxide                                                 glyceryl stearate                                                                          PEG-100 stearate                                                 myristyl lactate                                                                           cetyl alcohol                                                    carbomer-940 DMDM hydantoin                                                   fragrance    methylparaben                                                    propylparaben                                                                              quaternium-15                                         Pharmacist assessment:                                                                     This preparation was very slow to                                             vanish. One would have to rub the                                             area much longer than with other                                              lotion. The occlusion was not as                                              good as some of the other lotions.                                            Fragrant was pleasant and texture                                             smooth.                                                          Patient's assessment:                                                                     This preparation was generally accepted                                       well. The only complaint was the                                              messiness during to slow absorption when                                      applied.                                                          ______________________________________                                        FORMULA #17                                                                              α1-PI                                                                   Na Chloride 0.65% Na phosphate                                                polyethylene glycol sucrose                                                                     quaterium-I5                                     Pharmacist assessment:                                                                     A fine mist sprayer was used to apply                                         this solution. It was easy to apply                                           and could cover large or badly                                                abraded areas. After the solution                                             dried one would need to occlude                                               the area with an ointment or lotion.                                          The advantage to this system is less                                          α1-PI was needed to get the desired                                     therapeutic effect.                                              Patient's assessment:                                                                     The patients were able to apply the Alpha-                                    1-PI using this method without much                                           trouble. Some did not like using two                                          procedures to apply the drug. Patients                                        with very sore hands had some difficulties                                    working the sprayer.                                              ______________________________________                                        FORMULA #18                                                                              α1-PI                                                                   sterile water                                                                              Na chloride                                                      Na phosphate polyethyleneglycol                                               sucrose      quaternium-15                                         Pharmacist assessment:                                                                     A fine mist sprayer was used to apply                                         this solution. It was easy to apply                                           and could cover large and badly                                               abraded areas. After the solution                                             dried one would need to occlude the                                           area with an ointment or lotion. The                                          advantage to this system is less                                              α1-PI was needed to get the desired                                     therapeutic effect.                                              Patient's assessment:                                                                     The patients were able to apply the α1-PI                               using this method without much trouble.                                       Some did not like using two procedures to                                     apply the drug. Patients with very sore                                       hands had some difficulties working the                                       sprayer.                                                          ______________________________________                                        FORMULA #19                                                                              α1-PI                                                                   NaCl 0.65%    Na phosphate                                                    benzyl alcohol 1%                                                                           sucrose                                                         polyethylene glycol                                                                         quaternium-15                                        Pharmacist assessment:                                                                     A fine mist sprayer was used to apply                                         this solution. It was easy to apply                                           and could cover large or badly                                                abraded areas. After the solution                                             dried one would need to occlude the                                           area with an ointment or lotion. The                                          advantage to this system is less                                              Alpha-1-PI was needed to get the                                              desired therapeutic effect. The                                               benzyl was added as a preservative.                              Patient's assessment:                                                                     The patients were able to apply the Alpha-                                    1-PI using this method without much                                           trouble. Some did not like using two                                          procedures to apply the drug. Patients                                        with very sore hands had some difficulties                                    working the sprayer. Some of the patients                                     complained that this solution would burn                                      or irritate the skin. We determined this                                      problem was due to the benzyl alcohol.                            ______________________________________                                        FORMULA #20                                                                              α1-PI                                                                   hydroxypropyl methylcellulose 2910 1%                                         benzalkonium cl. 0.01%                                                        diabasic sodium phosphate                                                     monobasic sodium phosphate                                                    sodium citrate                                                                sodium chloride                                                               purified water                                                     Pharmacist assessment:                                                                     This preparation was used as a drop                                           application. The solution was easy                                            to apply and would spread easily. It                                          took only a minute or so for the                                              solution to dry. We did not intend                                            to occlude with an ointment. The                                              solution seemed to cause some drying                                          of the area when applied.                                                     Therapeutic effect was still good in                                          spite of the drying.                                             Patient's assessment:                                                                     It was easy to use. Some of the patients                                      did not like the drying effect of this                                        preparation.                                                      ______________________________________                                        FORMULA #21                                                                              α1-PI                                                                   polyvinyl alcohol 1.4%                                                                        povidone 0.6%                                                 chlorobutanol 0.5%                                                                            purified water                                                sodium chloride NaOH or HCI for pH                                            barquat                                                            Pharmacist assessment:                                                                     This preparation was used as a drop                                           application. The solution was easy                                            to apply and would spread easily. It                                          took only a minute or so for the                                              solution to dry. We did not intend                                            to occlude with an ointment. The                                              solution seemed to cause some drying                                          of the area when applied.                                        Patient's assessment:                                                                     It was easy to use. Some of the patient's                                     did not like the drying effect of this                                        preparation.                                                      ______________________________________                                    

It did not appear to make any difference as to the vehicle utilized forthe quaternary ammonium salt to aid in penetration of ∝1-PI.

We claim:
 1. In a pharameceutical composition for the topical treatmentof a mammal having a skin disease in which said composition contains aneffective amount of α-1-antitrypsin and a non-aqueous lipid misciblecarrier the improvement which comprises said composition containing aneffective amount of benzalkonium chloride at an effective concentrationfor increasing the chemical stability and, penetration of said proteaseinhibitor in the skin.